CA2539824C - Surface immobilized polyelectrolyte with multiple functional groups capable of covalently bonding to biomolecules - Google Patents
Surface immobilized polyelectrolyte with multiple functional groups capable of covalently bonding to biomolecules Download PDFInfo
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- G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
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Abstract
A polyelectrolyte having multiple exposed functional groups, each such group being capable of covalently bonding to a molecule, is immobilized on a surface for the purpose of bonding to a biomolecule. The biomolecule can be, for example, a nucleic acid, e.g., an amine functionalized oligonucleotide. The polyelectrolyte can include, e.g., BSA (Bovine Serum Albumin) which is bound to a functionalized surface using a covalent immobilization strategy, e.g., reaction with the surface of a tosyl-activated microparticle. Following such reaction, exposed reactive functional groups on the protein, such as amine, carboxyl, thiol, hydroxyl groups can further be utilized to covalently couple the oligonucleotide of interest using suitable chemistry.
Description
Surface Immobilized Polyelectrolyte with Multiple Functional Groups Capable of Covalently Bonding to Blomolecules Field of the Invention This invention is in the field of polyelectrolyte chemistry.
Background Field of the invention As an alternative to solve many of the problems associated with diagnostic use of "spotted arrays" of oligonucleotides (the problems are outlined in "Multianalyte Molecular Analysis Using Application-Specific Random Particle Arrays, "U.S. Application Serial No. 10/204,799, filed on 8/23/2002; WO
01/98765) preferred arrays are formed by binding oligonucleotide probes to encoded microbead particles, including, encoded particles made of polymer resin. See U. S. Patent Application Serial No. 10/271,602 "Multiplexed Analysis of Polymorphic Loci by Concurrent Interrogation and Enzyme-Mediated Detection," published as U.S. Publication No. 2004/0002073 Al, filed 10/15/2002, and Serial No. 10/204,799 supra. The encoded particle- probe conjugates are then assembled in a 2D array format and placed in contact with samples anticipated to contain target polynucleotides with subsequences complementary to the probes, where the target polynucleotides in the samples were previously fluorescently labeled. Binding between the probes and targets is determined by the presence of a fluorescent assay signal. Particular probes generating a positive assay signal can be determined by decoding the array.
There are several known and commercially available methods for attachment of oligonucleotide probes to microbeads. A great number of covalent immobilization schemes for oligonucleotide probes to microparticles have been devised and are available either in open literature or commercially.
Traditional covalent immobilization techniques use functionalized beads (i.e, beads functionalized with reactive groups like amino, carboxyl, tosyl, aldehyde, epoxy, hydrazide and others) to link to complementary functional groups on the end of oligonudeotide probes (Maire K. Walsh, Xinwen Wang and Bart C. Weimer, Optimizing the immobilization of single-stranded DNA onto glass beads, J.
Biochem. Biophys. Methods 2001; 47:221-231). Often times such binding protocols lead to improper orientation and steric hindrance problems. The hybridization performance of such covalently immobilized probes can be improved by introduction of spacer molecules (Edwin Southern, Kalim Mir and Mikhail Shchepinov; Molecular Interactions on Microarrays. Nature Genetics Supplement, 21, 1999, pp. 5-9), however, implementation is often difficult and impractical.
A practical and robust probe binding chemistry is therefore important for the optimal performance of a microbead array based assay. The chemistry must allow the probes to bind to the particles with high efficiency, in order to maintain a consistent concentration of probes on the bead surface and also the reaction must not alter the efficiency of probe-target binding. Moreover, the reaction must have minimum batch to batch variability . In one commonly used method, functionalized microparticles are coated with Neutravidin (Pierce, Rockford, IL), streptavidin or avidin, which are biotin binding proteins, to mediate immobilization of biotinylated probes. The avidin¨biotin interaction is highly specific and one of the strongest known (with an association constant (KA) of the order of 1015 M-1 in aqueous solutions) and provides nearly irreversible linkage between the bead surface immobilized protein and the biotinylated probe molecule. See U.S.
Patent Application Serial No. 10/271,602, supra. The method described below for binding probes to polyelectrolytes are preferred to these known methods, because they were demonstrated as capable of inducing attachment of greater numbers of oligonucleotides to beads.
Summary A polyelectrolyte having multiple exposed functional groups, each such group being capable of covalently bonding to a molecule, is immobilized on a surface for the purpose of bonding to a biomolecule. The biomolecule can be, for example, a nucleic acid, e.g., an amine functionalized oligonucleotide. The polyelectrolyte can include, e.g., BSA (Bovine Serum Albumin) which is bound to a functionalized surface using a covalent immobilization strategy, e.g., reaction with the surface of a tosyl-activated microparticle. Following such reaction,
Background Field of the invention As an alternative to solve many of the problems associated with diagnostic use of "spotted arrays" of oligonucleotides (the problems are outlined in "Multianalyte Molecular Analysis Using Application-Specific Random Particle Arrays, "U.S. Application Serial No. 10/204,799, filed on 8/23/2002; WO
01/98765) preferred arrays are formed by binding oligonucleotide probes to encoded microbead particles, including, encoded particles made of polymer resin. See U. S. Patent Application Serial No. 10/271,602 "Multiplexed Analysis of Polymorphic Loci by Concurrent Interrogation and Enzyme-Mediated Detection," published as U.S. Publication No. 2004/0002073 Al, filed 10/15/2002, and Serial No. 10/204,799 supra. The encoded particle- probe conjugates are then assembled in a 2D array format and placed in contact with samples anticipated to contain target polynucleotides with subsequences complementary to the probes, where the target polynucleotides in the samples were previously fluorescently labeled. Binding between the probes and targets is determined by the presence of a fluorescent assay signal. Particular probes generating a positive assay signal can be determined by decoding the array.
There are several known and commercially available methods for attachment of oligonucleotide probes to microbeads. A great number of covalent immobilization schemes for oligonucleotide probes to microparticles have been devised and are available either in open literature or commercially.
Traditional covalent immobilization techniques use functionalized beads (i.e, beads functionalized with reactive groups like amino, carboxyl, tosyl, aldehyde, epoxy, hydrazide and others) to link to complementary functional groups on the end of oligonudeotide probes (Maire K. Walsh, Xinwen Wang and Bart C. Weimer, Optimizing the immobilization of single-stranded DNA onto glass beads, J.
Biochem. Biophys. Methods 2001; 47:221-231). Often times such binding protocols lead to improper orientation and steric hindrance problems. The hybridization performance of such covalently immobilized probes can be improved by introduction of spacer molecules (Edwin Southern, Kalim Mir and Mikhail Shchepinov; Molecular Interactions on Microarrays. Nature Genetics Supplement, 21, 1999, pp. 5-9), however, implementation is often difficult and impractical.
A practical and robust probe binding chemistry is therefore important for the optimal performance of a microbead array based assay. The chemistry must allow the probes to bind to the particles with high efficiency, in order to maintain a consistent concentration of probes on the bead surface and also the reaction must not alter the efficiency of probe-target binding. Moreover, the reaction must have minimum batch to batch variability . In one commonly used method, functionalized microparticles are coated with Neutravidin (Pierce, Rockford, IL), streptavidin or avidin, which are biotin binding proteins, to mediate immobilization of biotinylated probes. The avidin¨biotin interaction is highly specific and one of the strongest known (with an association constant (KA) of the order of 1015 M-1 in aqueous solutions) and provides nearly irreversible linkage between the bead surface immobilized protein and the biotinylated probe molecule. See U.S.
Patent Application Serial No. 10/271,602, supra. The method described below for binding probes to polyelectrolytes are preferred to these known methods, because they were demonstrated as capable of inducing attachment of greater numbers of oligonucleotides to beads.
Summary A polyelectrolyte having multiple exposed functional groups, each such group being capable of covalently bonding to a molecule, is immobilized on a surface for the purpose of bonding to a biomolecule. The biomolecule can be, for example, a nucleic acid, e.g., an amine functionalized oligonucleotide. The polyelectrolyte can include, e.g., BSA (Bovine Serum Albumin) which is bound to a functionalized surface using a covalent immobilization strategy, e.g., reaction with the surface of a tosyl-activated microparticle. Following such reaction,
2 exposed reactive functional groups on the protein, such as amine, carboxyl, thiol, hydroxyl groups can further be utilized to covalently couple the oligonucleotide of interest using suitable chemistry.
In one embodiment, oligonucletides modified at a terminal position (the 3' or 5' terminal position) with amines (e.g., amino modified oligonucleotides) are covalently bound to BSA using an EDAC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) reaction (see, e.g., D. Seligal et al., Analytical Biochemistry 218:87091 (1994)). The covalent reaction results in the formation of an amide bond between the amine group at the terminus of the oligonucleotide and carboxyl groups on the BSA. The reaction is illustrated in Fig. 1.
The functionalized surface can be the surface of a bead or microparticle, which can be composed of any of a number of materials, including polymers, polymer resins, glass, latex or others which can be functionalized for immobilization of a polyelectrolyte. Experiments were performed comparing BSA-coated beads with human serum albumin ("NSA"), another exemplary polyelectrolyte, and with Neutravidin as well. The results of hybridization experiments indicated that the BSA-coated beads were capable of attaching greater concentrations of oligonucleotides to the beads.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates the bonding of BSA to functionalized beads and the bonding of an oligonucleotide probe to the BSA using an EDAC reaction.
Figs. 2 shows the hybridization signals from oligo-functionalized BSA
coupled beads as a function of the amount of added aminated probe for coupling.
A perfectly matching probe was attached to two sets of BSA-coupled beads. BSA
was coupled to the first set of beads at 65 C and to a second set at 37 C. A
much higher hybridization efficiency was noted (higher signal) on the first set of beads to which BSA was coupled at 65 C. A third set of beads coupled with BSA
at 65 C and functionalized with a mismatched negative control probe shows negligible hybridization, thus indicating that the enhanced signal is not a result of increased non-specific binding. Fig. 3 shows titration results of BSA coupled beads. As in Fig. 2,efficiency of hybridization is greater for the beads coupled
In one embodiment, oligonucletides modified at a terminal position (the 3' or 5' terminal position) with amines (e.g., amino modified oligonucleotides) are covalently bound to BSA using an EDAC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) reaction (see, e.g., D. Seligal et al., Analytical Biochemistry 218:87091 (1994)). The covalent reaction results in the formation of an amide bond between the amine group at the terminus of the oligonucleotide and carboxyl groups on the BSA. The reaction is illustrated in Fig. 1.
The functionalized surface can be the surface of a bead or microparticle, which can be composed of any of a number of materials, including polymers, polymer resins, glass, latex or others which can be functionalized for immobilization of a polyelectrolyte. Experiments were performed comparing BSA-coated beads with human serum albumin ("NSA"), another exemplary polyelectrolyte, and with Neutravidin as well. The results of hybridization experiments indicated that the BSA-coated beads were capable of attaching greater concentrations of oligonucleotides to the beads.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates the bonding of BSA to functionalized beads and the bonding of an oligonucleotide probe to the BSA using an EDAC reaction.
Figs. 2 shows the hybridization signals from oligo-functionalized BSA
coupled beads as a function of the amount of added aminated probe for coupling.
A perfectly matching probe was attached to two sets of BSA-coupled beads. BSA
was coupled to the first set of beads at 65 C and to a second set at 37 C. A
much higher hybridization efficiency was noted (higher signal) on the first set of beads to which BSA was coupled at 65 C. A third set of beads coupled with BSA
at 65 C and functionalized with a mismatched negative control probe shows negligible hybridization, thus indicating that the enhanced signal is not a result of increased non-specific binding. Fig. 3 shows titration results of BSA coupled beads. As in Fig. 2,efficiency of hybridization is greater for the beads coupled
3 with BSA at a higher temperature than at a lower temperature, as demonstrated by the difference in hybridization signal from a target placed in contact with an oligonucleotide probe bound to BSA-coupled beads where BSA was coupled to one set of beads at 37 C, and where BSA was coupled to another set of beads at 65 C. (see Example 4) Fig.4 indicates a differences in coupling efficiency of BSA to tosyl functionalized beads , at different temperatures, as determined using a hybridization assay, where oligonucleotide probes are bound to the BSA
immobilized on the beads and then reacted with a complementary fluorescently labeled target. (see Example 6) Fig. 5 indicates that for incubation at 65 C or higher for about 1 hour, for the coupling reaction of BSA to tosyl activated beads, the binding efficiency of BSA to the bead surface is not affected, as demonstrated by the difference in hybridization signal from a target placed in contact with an oligonucleotide probe bound to BSA-coupled beads. (see Example 7) Fig. 6A shows that BSA coated tosyl functionalized beads give a more uniform and stronger hybridization signal, following bonding of probes and hybridization with a target, than a Neutravidin-coated tosyl bead. (see Example 8) Fig. 6B shows the coefficient of variation of the signals in Fig. 6A.
Fig. 7 shows a significant difference in hybridization when HSA, rather than BSA, is the polyelectrolyte coated on tosyl functionalized beads, where oligonucleotide probes are bound, respectively, to BSA or HSA immobilized on beads, and then reacted with a complementary fluorescently labeled target.
Detailed Description Example 1: Preparation of BSA-Coated Tosyl Functionalized Beads BSA solution at the concentration of 5mg/mL is prepared by dissolving 50mg of BSA in 10mL of PBS. 2.0mL of PBS-T is added to a 15mL
centrifuge tube. 1mL of fluorescence colored beads at the concentration of 1%
solids (10mg) are transferred into the centrifuge tube, and mixed well by vortexing. The beads are spun down by centrifugation at 3,500 rpm for 4 +/-0.5
immobilized on the beads and then reacted with a complementary fluorescently labeled target. (see Example 6) Fig. 5 indicates that for incubation at 65 C or higher for about 1 hour, for the coupling reaction of BSA to tosyl activated beads, the binding efficiency of BSA to the bead surface is not affected, as demonstrated by the difference in hybridization signal from a target placed in contact with an oligonucleotide probe bound to BSA-coupled beads. (see Example 7) Fig. 6A shows that BSA coated tosyl functionalized beads give a more uniform and stronger hybridization signal, following bonding of probes and hybridization with a target, than a Neutravidin-coated tosyl bead. (see Example 8) Fig. 6B shows the coefficient of variation of the signals in Fig. 6A.
Fig. 7 shows a significant difference in hybridization when HSA, rather than BSA, is the polyelectrolyte coated on tosyl functionalized beads, where oligonucleotide probes are bound, respectively, to BSA or HSA immobilized on beads, and then reacted with a complementary fluorescently labeled target.
Detailed Description Example 1: Preparation of BSA-Coated Tosyl Functionalized Beads BSA solution at the concentration of 5mg/mL is prepared by dissolving 50mg of BSA in 10mL of PBS. 2.0mL of PBS-T is added to a 15mL
centrifuge tube. 1mL of fluorescence colored beads at the concentration of 1%
solids (10mg) are transferred into the centrifuge tube, and mixed well by vortexing. The beads are spun down by centrifugation at 3,500 rpm for 4 +/-0.5
4 minutes, and the supernatant is decanted. The beads are re-suspended by adding 3.0mL of PBST into the tube, and mixed well by vortexing. The beads are again spun down by centrifugation at 3,500 rpm for 4 +/- 0.5 minutes, and the supematant is discarded. 3.0mL of BSA solution (5 mg/mL) are added to the beads, and mixed well by vortexing. The tubes are placed on a shaker in a arc incubator, and the beads are allowed to react overnight with mixing at 250 rpm.
Thereafter, the beads are spun down by centrifugation at 3,500rpm for 4 minutes, and the supernatant is discarded. The beads are then washed by adding 3.0mL of PBS-T to the tube, and mixed on a vortex mixer. The beads are then again centrifuged at 3500 rpm for 4 +/- 0.5 minutes, and the supernatant is poured off. The washing and centrifuging steps are then repeated.
3.0mL of storage buffer (0.1M PBS containing 0.1% NaN3), are added, and mixed on a vortex mixer. The beads are again centrifuged at 3,500 rpm for 4 +/- 0.5 minutes, and the supematant is poured off. The beads are then resuspended in 1 ml of storage buffer by vortexing. The beads are at a concentration of 1% solids (10mg/mL), and are stored at 4-6 C. They are ready for attachment of amine-containing biomaterials (e.g., BSA) through the EDAC
reaction, as described below in Example 3.
Example 2: Preparation of BSA-Coated Carboxyl Functionalized Beads The coupling of BSA to carboxylated particles is carried out as :follows. 100 1 of carboxylated particles at a concentration of 1% solids is transferred to a 2m1 Eppendorf* tube. The beads are then pelleted by centrifugation and the supernatant removed. Following this, the beads are washed lx with 1m1 of MES (details) buffer (pH 4.5). Separately a stock solution of BSA (5mg BSA/ml) in MES buffer and EDC (20nig/m1) in MES buffer are prepared. 100 I of the BSA stock solution is added to the bead pellet and the suspension mixed well by vortexing. Following this, 4001.tI of the EDC stock solution is added to the bead suspension, mixed well by vortexing and allowed to react a room temperature for lhr with end-over-end mixing. After ihr incubation, 100 .1 of PBS-T is added to the suspension and the beads centrifuged. The * Trade-mark
Thereafter, the beads are spun down by centrifugation at 3,500rpm for 4 minutes, and the supernatant is discarded. The beads are then washed by adding 3.0mL of PBS-T to the tube, and mixed on a vortex mixer. The beads are then again centrifuged at 3500 rpm for 4 +/- 0.5 minutes, and the supernatant is poured off. The washing and centrifuging steps are then repeated.
3.0mL of storage buffer (0.1M PBS containing 0.1% NaN3), are added, and mixed on a vortex mixer. The beads are again centrifuged at 3,500 rpm for 4 +/- 0.5 minutes, and the supematant is poured off. The beads are then resuspended in 1 ml of storage buffer by vortexing. The beads are at a concentration of 1% solids (10mg/mL), and are stored at 4-6 C. They are ready for attachment of amine-containing biomaterials (e.g., BSA) through the EDAC
reaction, as described below in Example 3.
Example 2: Preparation of BSA-Coated Carboxyl Functionalized Beads The coupling of BSA to carboxylated particles is carried out as :follows. 100 1 of carboxylated particles at a concentration of 1% solids is transferred to a 2m1 Eppendorf* tube. The beads are then pelleted by centrifugation and the supernatant removed. Following this, the beads are washed lx with 1m1 of MES (details) buffer (pH 4.5). Separately a stock solution of BSA (5mg BSA/ml) in MES buffer and EDC (20nig/m1) in MES buffer are prepared. 100 I of the BSA stock solution is added to the bead pellet and the suspension mixed well by vortexing. Following this, 4001.tI of the EDC stock solution is added to the bead suspension, mixed well by vortexing and allowed to react a room temperature for lhr with end-over-end mixing. After ihr incubation, 100 .1 of PBS-T is added to the suspension and the beads centrifuged. The * Trade-mark
5 pellet is washed twice with 1m1 PBS-T by centrifugation-redispersion cycle, and the beads are finally suspended in 100 ,1 of storage buffer (0.1M PBS
containing 0.1% sodium azide, NaN3) and stored at 4-6 C.
Example 3: EDAC Reaction for Coupling of Aminated Oligonucletide Probes to BSA Beads The coupling of aminated oligonucletide probes to the beads, prepared as in Example 1 and 2, was carried out as followsA series of 1.5ml Eppendorf tubes were taken and labeled to identify the type of microparticle and the oligonucletide probe to be coupled. Following this, 500,uL of PBST was dispensed into each tube, followed by 100,uL of BSA coupled beads at concentration of 1% solids. The tubes were mixed well with a vortex mixer for seconds. The beads were then spun down at 9500rpm for 2 +/- 0.5 min, and the supernatant discarded. A 500pL aliquot of 0.05M MES buffer (pH4.5) was added to the pellet, and mixed well by vortexing. The beads were then centrifuged at 9500 rpm for 2 +/- 0.5 minutes, and the supernatant discarded. A 500u1 aliquot of 0.05M of EDAC in MES buffer (prepared right before use) was added to the beads, and mixed well by vortexing. ' Following 10,uL each of amino modified DNA probes (e.g., probe MS-508 N25, purchased from Integrated DNA
Technologies, Inc., Coralville IA) was added at a concentration of 100pM to each of the tubes containing the bead suspensions, and mixed well. The reaction is allowed to proceed for 1 hour at room temperature (20 - 25 C) with end-over-end mixing.
After the incubation, 100pL of PBS-T is added to each tube, and mixed by vortexing. The beads are then spun down in a centrifuge at 9500 rpm for 2 +/- 0.5 minutes, and the supernatant discarded. The beads are then washed twice with 500u1 PBS-T using the centrifugation redispersion cycle.
The beads are resuspended in 100pL of PBST to bring the final concentration to 11)/0 solids, and stored at 4-6 Cfor further use.
containing 0.1% sodium azide, NaN3) and stored at 4-6 C.
Example 3: EDAC Reaction for Coupling of Aminated Oligonucletide Probes to BSA Beads The coupling of aminated oligonucletide probes to the beads, prepared as in Example 1 and 2, was carried out as followsA series of 1.5ml Eppendorf tubes were taken and labeled to identify the type of microparticle and the oligonucletide probe to be coupled. Following this, 500,uL of PBST was dispensed into each tube, followed by 100,uL of BSA coupled beads at concentration of 1% solids. The tubes were mixed well with a vortex mixer for seconds. The beads were then spun down at 9500rpm for 2 +/- 0.5 min, and the supernatant discarded. A 500pL aliquot of 0.05M MES buffer (pH4.5) was added to the pellet, and mixed well by vortexing. The beads were then centrifuged at 9500 rpm for 2 +/- 0.5 minutes, and the supernatant discarded. A 500u1 aliquot of 0.05M of EDAC in MES buffer (prepared right before use) was added to the beads, and mixed well by vortexing. ' Following 10,uL each of amino modified DNA probes (e.g., probe MS-508 N25, purchased from Integrated DNA
Technologies, Inc., Coralville IA) was added at a concentration of 100pM to each of the tubes containing the bead suspensions, and mixed well. The reaction is allowed to proceed for 1 hour at room temperature (20 - 25 C) with end-over-end mixing.
After the incubation, 100pL of PBS-T is added to each tube, and mixed by vortexing. The beads are then spun down in a centrifuge at 9500 rpm for 2 +/- 0.5 minutes, and the supernatant discarded. The beads are then washed twice with 500u1 PBS-T using the centrifugation redispersion cycle.
The beads are resuspended in 100pL of PBST to bring the final concentration to 11)/0 solids, and stored at 4-6 Cfor further use.
6 The hybridization performance (see Example 4 for protocol) of oligonucleotide functionalized particles as a function of added amount of oligo (0.25, 0.5, 1, 2, 4, 8 ul of 100uM/ 20Oug particles) is shown in Fig. 2. The amount described above 10u1 of 100uM/1mg thus represents a saturation concentration.
Also, the beads with BSA coupled at higher temperature show improved hybridization performance as described in detail later.
Example 4: Hybridization Assay Using Oligonucletide Functionalized Beads 1. Bead mixtures are assembled on 8 different chips. Stock fluorescently labeled DNA target solution (MS508-90mer-CY5) is prepared in hybridization buffer (lx TMAC. Eight different serial dilutions are prepared from the stock target solution. 20 I of each of the serially diluted target solutions are then added to the eight separate chips.
2. A slide, containing the chips, is placed in a hybridization heater/shaker, and incubated at 55 C for 20minutes at 100rpnn.
3. The slide is removed and cooled to room temperature, and the hybridization solution is removed with the transfer pipette.
4. 20 I of 1X TMAC is added to each chip, and the chip is washed by pipetting the solution 8 to 10 times.
5. The washing solution is removed and 5m1 of mounting solution (1XTMAC) is added to each chip, and the assay signal (CY5) is read under a fluorescent microscope using a coverslip.
6. A titration curve is plotted of the hybridization signal (CY5) vs DNA probe concentration.
Example of titration curves are shown in Fig. 3.
Example 5 Experiments were conducted to compare the effect of adding EDAC
to the bead-probe suspension twice (EDAC is known to hydrolyze very quickly at acidic pH) to assess whether this leads to an enhanced binding of probes to the BSA layer. First, the probe MS-508-N25 was coupled to BSA-coated beads under each of the following condition: (10p,I 100 M probe/100 I 1% beads). One-half of
Also, the beads with BSA coupled at higher temperature show improved hybridization performance as described in detail later.
Example 4: Hybridization Assay Using Oligonucletide Functionalized Beads 1. Bead mixtures are assembled on 8 different chips. Stock fluorescently labeled DNA target solution (MS508-90mer-CY5) is prepared in hybridization buffer (lx TMAC. Eight different serial dilutions are prepared from the stock target solution. 20 I of each of the serially diluted target solutions are then added to the eight separate chips.
2. A slide, containing the chips, is placed in a hybridization heater/shaker, and incubated at 55 C for 20minutes at 100rpnn.
3. The slide is removed and cooled to room temperature, and the hybridization solution is removed with the transfer pipette.
4. 20 I of 1X TMAC is added to each chip, and the chip is washed by pipetting the solution 8 to 10 times.
5. The washing solution is removed and 5m1 of mounting solution (1XTMAC) is added to each chip, and the assay signal (CY5) is read under a fluorescent microscope using a coverslip.
6. A titration curve is plotted of the hybridization signal (CY5) vs DNA probe concentration.
Example of titration curves are shown in Fig. 3.
Example 5 Experiments were conducted to compare the effect of adding EDAC
to the bead-probe suspension twice (EDAC is known to hydrolyze very quickly at acidic pH) to assess whether this leads to an enhanced binding of probes to the BSA layer. First, the probe MS-508-N25 was coupled to BSA-coated beads under each of the following condition: (10p,I 100 M probe/100 I 1% beads). One-half of
7 the beads were removed from the lx tube after one hour of reaction time, and fresh EDAC was added, and then the reaction proceeded in this tube for one additional hour. The whole process was then repeated for the non-matching probe SSP 36. Each set of beads were pooled with the non-specific beads and assembled on a chip, and then all sets were placed in contact with target MS
508-40mer -Cy5 under hybridizing conditions. Results were then recorded, and are summarized below in Table II. 2X EDAC addition provided higher hybridization signals.
Table ll Model Assay Non-Probe Cy5 specific Concentration Signal CV Cy5 Signal CV
1X EDAC 536.1 0.17 79.9 0.26 2X extra EDAC 732.9 0.17 53.3 0.19 Example 6: BSA Coupling to Tosyl Activated Beads at Different Temperatures and Their Hybridization Characteristics 2.0mL of PBST was added to each of five 15mL centrifuge tubes and 1mL
of fluorescence colored beads, at the concentration of 1% solids (10mg), was added to each tube, and then the beads were mixed by vortexing. The beads were spun down by centrifugation at 3,500 rpm for 4 +/- 0.5 minutes, and the supernatant was decanted. The beads were then resuspended in 3.0mL of PBST, mixed well by vortexing, and again spun down by centrifugation at 3,500 rpm for 4 +/- 0.5 minutes. The supernatant was then poured off.
2mL of PBS (pH7.2) and 1mL of BSA solution (50mg/mL in PBS) was added to each tube, and mixed well by vortexing. The ambient temperature in an incubator for each of the tubes was set as follows: tube A - 22 C, tube B - 37 C,
508-40mer -Cy5 under hybridizing conditions. Results were then recorded, and are summarized below in Table II. 2X EDAC addition provided higher hybridization signals.
Table ll Model Assay Non-Probe Cy5 specific Concentration Signal CV Cy5 Signal CV
1X EDAC 536.1 0.17 79.9 0.26 2X extra EDAC 732.9 0.17 53.3 0.19 Example 6: BSA Coupling to Tosyl Activated Beads at Different Temperatures and Their Hybridization Characteristics 2.0mL of PBST was added to each of five 15mL centrifuge tubes and 1mL
of fluorescence colored beads, at the concentration of 1% solids (10mg), was added to each tube, and then the beads were mixed by vortexing. The beads were spun down by centrifugation at 3,500 rpm for 4 +/- 0.5 minutes, and the supernatant was decanted. The beads were then resuspended in 3.0mL of PBST, mixed well by vortexing, and again spun down by centrifugation at 3,500 rpm for 4 +/- 0.5 minutes. The supernatant was then poured off.
2mL of PBS (pH7.2) and 1mL of BSA solution (50mg/mL in PBS) was added to each tube, and mixed well by vortexing. The ambient temperature in an incubator for each of the tubes was set as follows: tube A - 22 C, tube B - 37 C,
8 tube - 50 C, tube D - 65 C and tube E - 75 C, and the beads were allowed to react with BSA for 14 hours at the designated temperature, with end-over-end mixing. The tubes were then cooled to room temperature, and the beads spun down by centrifugation at 3,500rpm for 4 minutes, and the supernatant poured off. The beads were then washed by adding 3.0mL of PBST to the tube, mixed on a vortex mixer, and spun down at 3500 rpm for 4 +/- 0.5 minutes. The supernatant was poured off.
1mL of storage buffer (PBS containing 0.1% NaN3) was added, and the tubes were mixed on a vortex mixer. The bead concentration was 1% solids (10mg/mL). The BSA coupled beads were stored at 4-6 C.
The 25-mer MS-508 N25 biotinylated oligonucleotide probe was conjugated to each set of beads through the EDAC coupling method described above. Each set of beads was then contacted with a fixed concentration of labeled target (a 90-mer oligonucleotide labeled with Cy-5) for the probe under hybridizing conditions. The quantity of label on the beads correlates with the probe concentration on the beads.
As shown in Fig. 4, the beads which were coupled to BSA at higher temperatures displayed more target binding to the oligonucleotide probes displayed on the bead surface.
This indicates that there is a greater concentration of probes at the surface of such beads, which may be because at 65 C, BSA denatures and opens up, presenting more available binding sites to the probes.
Example 7 Comparison of Varying Incubation Time for BSA Coupling to Tosyl Functionalized Particles An Experiment was conducted to study the time course of BSA coupling reaction on tosylated particles. Following the same protocol as in Examples 1 and 5 above, 12 separate tubes, each containing a BSA-tosyl particle reaction mixture, were incubated at 65 C in an oven, and one control tube was incubated at 37 C. Each tube was taken out after a predetermined incubation period, washed and then coupled with a oligonucleotide probe (including one control probe) following method outlined in Example 3. Following this, a hybridization
1mL of storage buffer (PBS containing 0.1% NaN3) was added, and the tubes were mixed on a vortex mixer. The bead concentration was 1% solids (10mg/mL). The BSA coupled beads were stored at 4-6 C.
The 25-mer MS-508 N25 biotinylated oligonucleotide probe was conjugated to each set of beads through the EDAC coupling method described above. Each set of beads was then contacted with a fixed concentration of labeled target (a 90-mer oligonucleotide labeled with Cy-5) for the probe under hybridizing conditions. The quantity of label on the beads correlates with the probe concentration on the beads.
As shown in Fig. 4, the beads which were coupled to BSA at higher temperatures displayed more target binding to the oligonucleotide probes displayed on the bead surface.
This indicates that there is a greater concentration of probes at the surface of such beads, which may be because at 65 C, BSA denatures and opens up, presenting more available binding sites to the probes.
Example 7 Comparison of Varying Incubation Time for BSA Coupling to Tosyl Functionalized Particles An Experiment was conducted to study the time course of BSA coupling reaction on tosylated particles. Following the same protocol as in Examples 1 and 5 above, 12 separate tubes, each containing a BSA-tosyl particle reaction mixture, were incubated at 65 C in an oven, and one control tube was incubated at 37 C. Each tube was taken out after a predetermined incubation period, washed and then coupled with a oligonucleotide probe (including one control probe) following method outlined in Example 3. Following this, a hybridization
9 reaction was performed and the assay intensity was recorded (see Example 4).
The results are shown in Fig. 5 which illustrates that the BSA coupling reaction is essentially complete in less than one hour.
Example 8: Comparison with Conventional Biotin-Avidin Oligonucleotide Coupling and NeutrAvidin Coating Chemistry An experiment was carried out to compare the capture and hybridization efficiency of oligo-conjugated, BSA-functionalized beads with biotinylated oligo-conjugated NeutrAvidin bead. The proteins were coupled to the bead surface at 37 C using a protocol as outlined in Example 1. Following this, biotinylated (and also aminated) oligos were conjugated to particles (as in Example 3) and a hybridization assay was carried out with a cognate target.
Two differently encoded but otherwise identical BSA coated particles were taken and a matching probe was bound to one group and a non-matching probe was bound to the other group. Similarly two other NeutrAvidin-functionalized beads were taken and bound to matched and mismatched biotinylated probes.
The results of the assay are shown in Figs. 6A and 6B. It is evident that BSA coating provides a more uniform (lower CV) and higher signal to noise ratio (the hybridization intensity on the mismatched probe was considered as noise) than achieved when using the NeutrAvidin capture chemistry.
Example 9: Comparison with HSA Coating HSA (Human Serum Albumin) was coupled under identical conditions to those used for BSA coupling to tosyl-functionalized particles. The HSA
functionalized particles were then coupled with oligonucleotide probes and hybridized (titrated) to a fluorescently labeled model DNA target (as in Example 4). The results are shown in Fig. 7. It indicates that the HSA coating is not as effective as the BSA coating for binding the oligonucleotide probes notwithstanding the fact that, like BSA, HSA has many functional carboxyl groups + available for binding to the oligonucleotide probes.
Example 10: Batch to Batch Variation of BSA Coupling Three batches of beads of 10mg/each were separately coupled with BSA at 65 C for 14 hours, where the BSA-bead ratio was 5 (W/VV, mg/mg). The reaction volume for coupling was 3mL. One batch of beads was coupled to BSA at 37 C for use as a control. The coupling efficiency was determined based on signal intensity for hybridization of DNA probes coupled to the beads to cognate targets.
The hybridization was done at 55 C for 20 minutes in 1X TMAC, and the target wasMS508-90mer-CY5 at a concentration of 400nM. The integration time for assay read-out is 200ms. The results are shown in Table I.
Table I
Batch CY5 Intensity (100ms) Control 3964 The 65 C batches had a consistently higher intensity than the batch coupled at 37 C and also the batch to batch variability was small.
The scope of the claims should not be limited by particular examples set forth herein, but should be construed in a manner consistent with the description as a whole.
The results are shown in Fig. 5 which illustrates that the BSA coupling reaction is essentially complete in less than one hour.
Example 8: Comparison with Conventional Biotin-Avidin Oligonucleotide Coupling and NeutrAvidin Coating Chemistry An experiment was carried out to compare the capture and hybridization efficiency of oligo-conjugated, BSA-functionalized beads with biotinylated oligo-conjugated NeutrAvidin bead. The proteins were coupled to the bead surface at 37 C using a protocol as outlined in Example 1. Following this, biotinylated (and also aminated) oligos were conjugated to particles (as in Example 3) and a hybridization assay was carried out with a cognate target.
Two differently encoded but otherwise identical BSA coated particles were taken and a matching probe was bound to one group and a non-matching probe was bound to the other group. Similarly two other NeutrAvidin-functionalized beads were taken and bound to matched and mismatched biotinylated probes.
The results of the assay are shown in Figs. 6A and 6B. It is evident that BSA coating provides a more uniform (lower CV) and higher signal to noise ratio (the hybridization intensity on the mismatched probe was considered as noise) than achieved when using the NeutrAvidin capture chemistry.
Example 9: Comparison with HSA Coating HSA (Human Serum Albumin) was coupled under identical conditions to those used for BSA coupling to tosyl-functionalized particles. The HSA
functionalized particles were then coupled with oligonucleotide probes and hybridized (titrated) to a fluorescently labeled model DNA target (as in Example 4). The results are shown in Fig. 7. It indicates that the HSA coating is not as effective as the BSA coating for binding the oligonucleotide probes notwithstanding the fact that, like BSA, HSA has many functional carboxyl groups + available for binding to the oligonucleotide probes.
Example 10: Batch to Batch Variation of BSA Coupling Three batches of beads of 10mg/each were separately coupled with BSA at 65 C for 14 hours, where the BSA-bead ratio was 5 (W/VV, mg/mg). The reaction volume for coupling was 3mL. One batch of beads was coupled to BSA at 37 C for use as a control. The coupling efficiency was determined based on signal intensity for hybridization of DNA probes coupled to the beads to cognate targets.
The hybridization was done at 55 C for 20 minutes in 1X TMAC, and the target wasMS508-90mer-CY5 at a concentration of 400nM. The integration time for assay read-out is 200ms. The results are shown in Table I.
Table I
Batch CY5 Intensity (100ms) Control 3964 The 65 C batches had a consistently higher intensity than the batch coupled at 37 C and also the batch to batch variability was small.
The scope of the claims should not be limited by particular examples set forth herein, but should be construed in a manner consistent with the description as a whole.
Claims (8)
1. A product comprising:
a. a microparticle;
b. a single layer coating of bovine serum albumin (BSA) that is covalently immobilized on a functionalized surface of the microparticle in a reaction carried out at a temperature of 65 °C or greater; and c. a nucleic acid covalently bound to the BSA.
a. a microparticle;
b. a single layer coating of bovine serum albumin (BSA) that is covalently immobilized on a functionalized surface of the microparticle in a reaction carried out at a temperature of 65 °C or greater; and c. a nucleic acid covalently bound to the BSA.
2. The product of claim 1, wherein the nucleic acid is an oligonucleotide.
3. The product of claim 2, wherein the oligonucleotide is bound to the BSA
through an amide linkage, formed by a reaction with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimde (EDAC).
through an amide linkage, formed by a reaction with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimde (EDAC).
4. The product of claim 2, wherein the oligonucleotide is biotinylated at its 5' terminus.
5. The product of claim 1, wherein the surface is the surface of a microparticle which is composed of a polymer, a polymer resin, glass or latex.
6. A process for bonding a nucleic acid to a polymer, polymer resin, glass or latex surface of a microparticle, the process comprising:
a. activating the microparticle surface with tosyl to obtain a functionalized surface;
b. covalently immobilizing bovine serum albumin (BSA) on the functionalized surface in a reaction carried out at a temperature of 65 °C or greater;
and c. covalently bonding a nucleic acid having a functionalized 3' or 5' end to said BSA using the functionalized end.
a. activating the microparticle surface with tosyl to obtain a functionalized surface;
b. covalently immobilizing bovine serum albumin (BSA) on the functionalized surface in a reaction carried out at a temperature of 65 °C or greater;
and c. covalently bonding a nucleic acid having a functionalized 3' or 5' end to said BSA using the functionalized end.
7. The process of claim 6, wherein the nucleic acid is an oligonucleotide functionalized with an amine group at the 5' terminus or biotinylated.
8. The process of claim 7, wherein the oligonucleotide is bound to the BSA
using an EDAC reaction, whereby an amide bond is formed between the oligonucleotide and the BSA.
using an EDAC reaction, whereby an amide bond is formed between the oligonucleotide and the BSA.
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WO2005031305A2 (en) | 2005-04-07 |
AU2004276761A1 (en) | 2005-04-07 |
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JP2007506108A (en) | 2007-03-15 |
EP1664722A4 (en) | 2007-10-31 |
WO2005031305A3 (en) | 2006-03-30 |
CN1882699A (en) | 2006-12-20 |
US20050260611A1 (en) | 2005-11-24 |
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